3-183152455-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014398.4(LAMP3):c.808G>A(p.Ala270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000595 in 1,613,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A270D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: LAMP3 NM_014398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.483

Genes affected

LAMP3 (HGNC:14582): (lysosomal associated membrane protein 3) Dendritic cells (DCs) are the most potent antigen-presenting cells. Immature DCs efficiently capture antigens and differentiate into interdigitating dendritic cells (IDCs) in lymphoid tissues that induce primary T-cell responses (summary by de Saint-Vis et al., 1998 [PubMed 9768752]).[supplied by OMIM, Dec 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022605062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAMP3	NM_014398.4	c.808G>A	p.Ala270Thr	missense_variant	3/6	ENST00000265598.8
LAMP3	XM_005247360.6	c.808G>A	p.Ala270Thr	missense_variant	4/7
LAMP3	XM_047447967.1	c.808G>A	p.Ala270Thr	missense_variant	3/6
LAMP3	XM_011512688.3	c.808G>A	p.Ala270Thr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAMP3	ENST00000265598.8	c.808G>A	p.Ala270Thr	missense_variant	3/6	1	NM_014398.4	P2
LAMP3	ENST00000466939.1	c.736G>A	p.Ala246Thr	missense_variant	3/6	2		A2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000411 AC: 103 AN: 250308 Hom.: 0 AF XY: 0.000466 AC XY: 63 AN XY: 135322

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000750

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000623 AC: 910 AN: 1460844 Hom.: 1 Cov.: 31 AF XY: 0.000610 AC XY: 443 AN XY: 726766

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000761

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74458

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000619 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000273

EpiControl AF: 0.00101

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.808G>A (p.A270T) alteration is located in exon 3 (coding exon 3) of the LAMP3 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the alanine (A) at amino acid position 270 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.029
Sift	Benign	0.099	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.21	B;.
Vest4		0.19
MVP		0.043
MPC		0.073
ClinPred		0.015	T
GERP RS		0.64
Varity_R		0.16
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115281513; hg19: chr3-182870243;